The broad objective of the proposed investigation is to increase our understanding of the biochemical parameters of the genetically- caused neurological disorder metachromatic leukodystrophy (MLD). The primary experimental model will be fibroblasts in culture derived from patients with different clinical forms of the disorder. Arylsulfatase A, the defective element in MLD, has a vital function in neuronal tissue as cerebroside sulfate sulfohydrolase. Different forms of the enzyme are produced in various clinical entities of the disease. The enzymes and the consequences of the deficiency will be studied in cell-free extracts, subcellular particulate matter, and in intact fibroblasts. We have established the feasibility of enzyme replacement as a therapeutic approach for MLD in the cultured cell system. Refinements of this approach as well as alternative approaches to therapy will be developed in the culture model. The experimental observations will facilitate early and accurate diagnosis of the different forms of the disorder, provide means for heterozygote identification, and enable formulation of rational and effective approaches to therapy.